Studies in rodents have demonstrated that adoptive immunotherapy with antigen specific T cells is effective for cancer and infections, and there is evidence this modality has therapeutic activity in humans1-8. For clinical applications, it is necessary to isolate T cells of a desired antigen specificity or to engineer T cells to express receptors that target infected or transformed cells, and then expand these cells in culture9-14. The transfer of T cell clones is appealing because it enables control of specificity and function, and facilitates evaluation of in vivo persistence, toxicity and efficacy. Additionally, in the setting of allogeneic stem cell transplantation, the administration to recipients of T cell clones from the donor that target pathogens or malignant cells can avoid graft-versus-host disease that occurs with infusion of unselected donor T cells3,4,15. However, it is apparent from clinical studies that the efficacy of cultured T cells, particularly cloned CD8+ T cells, is frequently limited by their failure to persist after adoptive transfer16,17.
The pool of lymphocytes from which CD8+ T cells for adoptive immunotherapy can be derived contains naïve and long-lived, antigen experienced memory T cells (TM). TM can be divided further into subsets of central memory (TCM) and effector memory (TEM) cells that differ in phenotype, homing properties and function's. CD8+ TCM express CD62L and CCR7, which promote migration into lymph nodes, and proliferate rapidly if re-exposed to antigen. CD8+ TEM lack CD62L enabling migration to peripheral tissues, and exhibit immediate effector function19.
In response to antigen stimulation, CD8+ TCM and TEM both differentiate into cytolytic effector T cells (TE) that express a high level of granzymes and perforin, but are short-lived20. Thus, the poor survival of T cells in clinical immunotherapy trials may simply result from their differentiation during in vitro culture to TE that are destined to die17,21,22.